Process for the production of anhydrosugar alcohols

ABSTRACT

A process is provided for the preparation of anhydrosugar alcohols. The process involves heating a sugar alcohol or a monoanhydrosugar alcohol starting material in the presence of an acid catalyst, and subsequent purification of the anhydrosugar alcohol. Very high purities are achieved, without the use of organic solvents in the process.

[0001] This application claims priority to provisional applicationserial No. 60/244962, filed on Nov. 01, 2000.

FIELD OF THE INVENTION

[0002] The present invention relates to the production of anhydrosugaralcohols. More particularly, the present invention relates to a processfor the production of anhydrosugar alcohols from sugar alcohols thatdoes not require the use of organic solvents.

BACKGROUND

[0003] The chemical formation of closed-ring organic molecules has posedmany issues for structural organic chemists. This has been particularlytrue with regard to synthetic reactions involving sugars and polyols,the acid dehydration of which leads to inernal anhydro compounds (mono-and dianhydro products). Fleche and Huchette, Staerke, 38 (1985) 26-30.

[0004] The earliest work in this area was done on1,4:3,6-dianhydro-D-mannitol by Fauconnier in 1884. Only sporadic workfollowed until the 1940's and 1950's, when intensive work was done onall possible isomers of 1,4:3,6-dianhydrohexitols. Stoss and Hemmer,Adv. Carbohydrate Chem. and Biochem. (1991) 93-173. Since then a largebody of chemical literature has developed in this area.

[0005] The 1,5:3,6-dianhydrohexitols belong to the so-called“biomass-derived substances”, obtainable from natural products.Therefore, these compounds are classified as “regenerable resources.”Furthermore, 1,4:3,6-dianhydrohexitols, such as isosorbide, can be usedas starting materials and intermediates in various organic syntheticreaction schemes. For example, isosorbide is useful in the formation ofnumerous pharmaceutical compounds, in food production, cosmeticproduction, plastic and polymer production, and in other industrial usessuch as in the production of polyurethane, polycarbonate, polyesters,and polyamides. Stoss and Hemmer, 1991.

[0006] Of the known isohexides, isosorbide is considered to be that ofthe highest importance. Stoss and Hemmer (1991) describe the putativesteps leading from D-glucitol (also referred to in the art as sorbitol)to isosorbide. Acidic media are generally used for dehydrating the sugaralcohol substrate. Especially to enhance the yield and to avoid sidereactions, certain modifications of the reaction conditions have beenemployed over the years, with various impacts on yield of isosorbideproduct. Stoss and Hemmer, 1991.

[0007] Several processes for the production of anhydrosugar alcohols(including isohexides such as isosorbide) are known. See, for example,PCT application number PCT/US99/00537 (WO 00/14081), collecting methodsand disclosing a continuous production method with recycling of organicsolvent. Most methods involve the use of concentrated acids and organicsolvents. Goodwin et al. (Carbohydrate Res. 79 (1980), 133-141) havedisclosed a method involving the use of acidic-cation-exchange resin inplace of concentrated, corrosive acids, but with low yield of isosorbideproduct. An alternative, supersaturation-based method is disclosed inU.S. Pat. No. 4,564,692 (Feldmann et al., Jan. 14, 1986). However, aneed continues in the art for a process for production of very pureisosorbide, at reasonable yields, and preferably without the use ofpotentially hazardous organic solvents.

SUMMARY OF THE INVENTION

[0008] The present invention relates to a process for the preparation ofanhydrosugar alcohols from sugar alcohol starting materials. The processresults in very pure products, with relatively high yields, without theuse of organic solvents.

[0009] In general, the process involves the heating of the appropriatesugar alcohol starting material, with stirring, until molten;dehydrating the molten starting material in the presence of anappropriate catalyst (e.g., a soluble acid or an acidic ion exchangeresin), with stirring, and under vacuum at elevated temperature;purifying the anhydrosugar alcohol, for example by distillation, andthen by melt crystallization and/or redistillation; and isolating thefinal, purified product (for example, by centrifugation or,alternatively, by filtration).

DETAILED DESCRIPTION

[0010] The present invention provides a solvent-free process for theproduction of very pure anhydrosugar alcohols. The process of theinvention generally includes the steps of melting a sugar alcoholstarting material, maintaining the elevated temperature and adding anappropriate catalyst and applying a vacuum, with stirring, for a lengthof time (which will depend upon the reaction conditions) sufficient toremove all water. The resultant anhydrosugar alcohol mixture is thensubjected to a purification and separation process, and an anhydrosugaralcohol product of high purity is produced.

[0011] Typical sugar alcohols, particularly pentites and hexites, aresuitable for use as starting materials in the process of the invention.The starting materials can include sugar alcohols, monoanhydrosugaralcohols, or a mixture of such alcohols. Generally the preferredstarting materials include arabinitol, ribitol, D-glucitol (alsoreferred to in the art as D-sorbitol or sorbitol, and referred to hereinas sorbitol), D-mannitol (or mannitol), galactitol (dulcitol), iditol,and the like. Sorbitol is a particularly preferred starting materialbecause it is readily available, and because pure isosorbide is veryuseful in a number of chemical and pharmaceutical applications.

[0012] In the first step of the process of the present invention, theselected starting material is melted. If, by way of example, sorbitol isthe starting material, it is heated to at least about 100° C., or atleast to its melting point. For anhydrosugar alcohols generally thistemperature is from about 100° C. to about 191°. For sorbitol powder, toprovide a specific example, the preferred melting temperature is fromabout 98° C. to about 105° C.; an even more preferred meltingtemperature is from about 98

C. to about 100

C. Once molten, the sorbitol is subjected to stirring.

[0013] A catalyst that will facilitate the dehydration of the sugaralcohol is then added to the molten starting material. Typically thecatalysts used to facilitate the dehydration of sugar alcohols are acidcatalysts. The classes of acid catalysts useful in the practice of thepresent invention are soluble acids, acidic ion resins, and inorganicion exchange materials. Therefore, acids such as sulfuric acid,phosphoric acid, p-toluenesulfonic acid, p-methanesulfonic acid, and thelike, are preferred for use in the present invention. Alternatively, forexample, Zeolite powders such as CBV 3024 or CBV 5534G (available fromZeolist International), or T-2665 or T-4480 (available from UnitedCatalysis, Inc.), or the like, can be used in the practice of theinvention. More preferred are acidic ion resins such as AG50W-X12 fromBioRad Laboratories, Amberlyst 15 or 35 from Rohm & Hass, and RCP21Hfrom Mitsubishi Chemical Corp., as well as Dowex 50Wx4 (Dow ChemicalCo.). Amberlyst 35 is a particularly preferred resin in the practice ofthe present invention, specifically for the production of isosorbidefrom sorbitol.

[0014] The amount of catalyst used will vary depending upon the reactionconditions and starting material, as those of skill in the art willappreciate, but will generally be on the order of from about 0.01equivalents to about 0.15 equivalents by weight. The currently preferredamount of catalyst is 0.1 equivalents by weight.

[0015] It is possible to perform one or two dehydrations of the startingsugar alcohol during the reaction, producing a mono- or dianhydrosugaralcohol. The reaction may also be controlled so as to produce acombination of mono- and dianhydrosugar alcohols by adjusting either thereaction conditions or the starting materials, which as those of skillin the art will appreciate, could contain both sugar alcohols andmonoanhydrosugar alcohols.

[0016] The dehydration in the presence of the catalyst is carried outunder a vacuum, at elevated temperatures, and with stirring of thereaction mixture. The vacuum can range over a pressure of from about0.05 Torr to about 40 Torr, with preferred pressures of from about 1Torr to about 10 Torr. As a specific example, the currently preferredpressure for the dehydration step in the process of the presentinvention in which isosorbide is made from sorbitol is from about 1 Torrto about 10 Torr. In the production of isosorbide from sorbitol, thedehydration is carried out for approximately 2 hrs, with constantstirring, at a temperature of about 120° C. The water is pulled off ofthe melted sorbitol/catalyst mixture under a vacuum of from about 1 Torrto about 10 Torr.

[0017] It will of course be appreciated by those of skill in the artthat, in a process such as that of the present invention, which involvesapplication of both elevated temperatures and vacuum, the specificparameters of the process, including the time it takes to carry certainsteps to completion, will vary depending upon the temperatures andpressures used. As one of skill in the art would anticipate, forexample, the inventors have determined that higher vacuum levels for thedistillation step gave the expected lower distillation temperature. Anadditional variable is the selected starting material, which will have aparticular melting and/or distillation point (the latter, of course,being dependent upon the vacuum). This is equally true for thepurification process described below. However, given the disclosurepresented herein, it is within the level of skill in the art to optimizethe process parameters of the invention for a particular application.This can be done with only a few preliminary experiments, and withoutundue experimentation, in light of the instant disclosure.

[0018] Following the dehydration procedure, the resultant mixture ispurified. In a preferred embodiment, vacuum distillation is used,although alternatives such as filtration, or the addition of activatedcharcoal with subsequent crystallization, are available. As noted above,the parameters for vacuum distillation will vary depending upon thematerial to be purified, and the temperature and pressure, as will beappreciated by those of ordinary skill in the art. The pot temperaturewill of course depend upon the temperature at which the material to bepurified distills (the distillation point), which again will depend onthe vacuum applied in the system. For example, in the case ofisosorbide, a range of vapor temperatures of from about 155° C. to about170° C. is preferred; more preferred is from about 160° C. to about 170°C.; even more preferred is from about 165° C. to about 170° C. Thevacuum pressure can be from about 0.05 Torr to about 40 Torr; preferablyfrom about 1 Torr to about 10 Torr. For example, and specifically withregard to vacuum distillation of isosorbide, a vacuum pressure of fromabout 1 Torr to about 10 Torr, a pot temperature of about 180° C. and avapor temperature of from about 160

C. to about 170° C. are currently most preferred.

[0019] In order to further purify and isolate the anhydrosugar alcohol,the anhydrosugar alcohol distillate is subjected to meltcrystallization. The recovered distillate product is heated to itsmelting point (e.g., for isosorbide, to approximately 65° C.) untilmolten, and then cooled over time until the crystallization point isreached, but not so much that the material solidifies. In fact, aslurry-like consistency is preferred, so that the material can becentrifuged. The centrifugation is performed at a relatively high speedfor a relatively short period of time, again in order to avoidsolidification of the material, and also to avoid having the desiredpurified anhydrosugar alcohol end product be drawn off with theremaining impurities. The resultant anhydrosugar alcohol product shouldbe at least 98% pure, and in most cases will be >99% pure (dependingupon the solidity of the “slurry”).

[0020] The present invention is described in further detail in thefollowing non-limiting examples.

EXAMPLE 1

[0021] This Example describes the production of very high purityisosorbide from sorbitol using a particularly preferred embodiment ofthe process of the present invention.

[0022] Sorbitol powder (180.6 grams, 0.99 mol) was placed in a 3-neckround bottom flask equipped with an agitator, temperature probe, andvacuum line. The sorbitol was heated to approximately 100° C. untilmolten. An acidic ion exchange resin, Amberlyst 35 (Rhom & Haas) (19.8grams) was added and vacuum was applied at from about 1 Torr to about 10Torr. The temperature was increased to from about 120° C. to about 130°C. These temperature and vacuum parameters were maintained forapproximately 2 hours, with constant stirring. The resultant mixture wasthen vacuum distilled at from about 1 Torr to about 10 Torr, pottemperature of 180° C., vapor temperature of 170° C. The distillate wascollected and subjected to melt crystallization by heating toapproximately 65° C. until molten, then cooling, over about 30 minutesto about 45 minutes to approximately 35° C., at which temperature aslurry-like solution was formed. This solution was then quicklycentrifuged (in order to avoid solidification), and the resultantisosorbide product had a purity of 99.3%, with an overall yield of 48%.

EXAMPLE 2

[0023] The same apparatus and the same operational conditions-exceptthose specified below-as in Example 1 were used. Upon heating sorbitolto ˜100° C. to a molten state, an acidic ion exchange resin, Amberlyst15 (Rohm and Haas, 24.2 g), was added and vacuumed applied (5-7 Torr).Heating was increased to 135° C. and the reaction allowed to stircontinuously for ˜2h. The resulting mixture contained 64.5% isosorbideand was then purified by the procedure described in Example 1.

EXAMPLE 3

[0024] The same apparatus and the same operational conditions-exceptthose specified below-as in Example 1 were used. Upon heating sorbitolto ˜100° C. to a molten state, an acidic ion exchange resin, Dowex50WX4, (18.1 g), was added and vacuumed applied (7-9 Torr). Heating wasincreased to 135° C. and the reaction allowed to stir continuously for˜2h. The reaction mixture contained 64.1% isosorbide. Purification wasthen performed.

EXAMPLE 4

[0025] The same apparatus and the same operational conditions-exceptthose specified below-as in Example 1 were used. Upon heating sorbitolto ˜100° C. to a molten state, the acidic ion exchange resin, Amberlyst35 (Rohm and Haas, 11.7 g), was added and vacuumed applied (9-12 Torr).Heating was increased to 135° C. and the reaction allowed to stircontinuously for ˜2h. The resulting mixture contained 18.6% sorbitan and73.4% isosorbide. The mixture was then purified using the abovedescribed procedure.

EXAMPLE 5

[0026] The same apparatus and the same operational conditions-exceptthose specified below-as in Example 1 were used. Upon heating sorbitolto ˜100° C. to a molten state, the acidic ion exchange resin, RCP21H(Mitsubishi Chemical Corporation, 12.9 g), was added and vacuumedapplied (7-9 Torr). Heating was increased to 135° C. and the reactionallowed to stir continuously under vacuum for ˜5h. The resulting mixturecontained 68.9% isosorbide. The mixture was then purified using theabove described procedure.

EXAMPLE 6

[0027] The same apparatus and operational conditions-except thosespecified below-as in Example 1 were used. Sorbitol (221.4 g, 0.99 mol)was heated to ˜100° C. to a molten state. At this time, a sulfatedzirconia pellet (#416/03 Japan Energy Corporation, 57.7 g), was addedand vacuumed applied (5-7 Torr). Heating was increased to 150° C. andthe reaction allowed to stir continuously for ˜7h. The resulting mixturecontained 2.2% sorbitol, 56.0% sorbitan and 22.9% isosorbide.

[0028] Having now fully described the present invention in some detailby way of illustration and example for purposes of clarity ofunderstanding, it will be obvious to one of ordinary skill in the artthat the invention can be performed by modifying or changing theinvention with a wide and equivalent range of conditions, formulationsand other parameters thereof. Furthermore, it will be obvious to theskilled practitioner that such modifications or changes are intended tobe encompassed within the scope of the appended claims.

[0029] All publications, patents and patent applications mentioned inthis specification are indicative of the level of skill of those skilledin the art to which this invention pertains, and are herein incorporatedby reference to the same extent as if each individual publication,patent or patent application was specifically and individually indicatedto be incorporated by reference.

What is claimed is:
 1. A process for the production of an anhydrosugaralcohol, without using organic solvents, the process comprising: heatinga selected sugar alcohol or monoanhydrosugar alcohol starting material,with stirring, until molten; dehydrating the starting material, undervacuum and while maintaining heat and stirring, in the presence of anacid catalyst to produce a dehydrated anhydrosugar alcohol mixture; andpurifying the anhydrosugar alcohol.
 2. The process of claim 1 whereinthe acid catalyst is a soluble acid.
 3. The process of claim 2 whereinthe acid catalyst is selected from the group consisting of sulfuricacid, phosphoric acid, p-toluenesulfonic acid, and p-methanesulfonicacid.
 4. The process of claim 1 wherein the acid catalyst is a zeolytepowder.
 5. The process of claim 4 wherein the zeolyte powder is selectedfrom the group consisting of CBV 3024, 5534G, T-2665, and T-4480.
 6. Theprocess of claim 1 wherein the acid catalyst is an acidic ion exchangeresin.
 7. The process of claim 6 wherein the acidic ion exchange resinis selected from the group consisting of AG50W-X12, Amberlyst 35,Amberlyst 15, RCP21H, and Dowex 50Wx4.
 8. The process of claim 6 whereinthe acidic ion exchange resin is added in an amount giving from about0.01 to about 0.15 gram equivalents of resin to sugar alcohol.
 9. Theprocess of claim 1 wherein the purification comprises vacuumdistillation of the dehydrated anhydrosugar alcohol mixture followed bymelt crystallization.
 10. The process of claim 1 wherein thepurification comprises vacuum distillation of the dehydratedanhydrosugar alcohol mixture followed by a re-distillation.
 11. Theprocess of claim 1, further comprising a final separation of theanhydrosugar alcohol by centrifugation.
 12. The process of claim 1,further comprising a final separation of the anhydrosugar alcohol byfiltration.
 13. A process for the production of an anhydrosugar alcohol,without using organic solvents, the process comprising: heating aselected sugar alcohol or monoanhydrosugar alcohol starting material,with stirring, until molten; dehydrating the molten starting material,under vacuum and while maintaining heat and stirring, in the presence ofan acid catalyst, to produce a dehydrated anhydrosugar alcohol mixture;vacuum distilling the dehydrated anhydrosugar alcohol mixture to producean anhydrosugar alcohol distillate; melt crystallizing the anhydrosugaralcohol distillate to produce a crystallized anhydrosugar alcoholproduct; and centrifuging the crystallized anhydrosugar alcohol productto produce a very pure anhydrosugar alcohol.
 14. The process of claim 13wherein the acid catalyst comprises a soluble acid.
 15. The process ofclaim 14 wherein the soluble acid is selected from the group consistingof sulfuric acid, phosphoric acid, p-toluenesulfonic acid, andp-methanesulfonic acid.
 16. The process of claim 13 wherein the acidcatalyst comprises a zeolyte powder.
 17. The process of claim 16 whereinthe zeolyte powder is selected from the group consisting of CBV 3024,CBV 5534G, T-2665, and T-4480.
 18. The process of claim 13 wherein theacid catalyst comprises an acidic ion exchange resin.
 19. The process ofclaim 18 wherein the acidic ion exchange resin is selected from thegroup consisting of CBV 3024, CBV 5534G, T-2665, T-4480, AG50W-X12,Amberlyst 15, Amberlyst 35, RCP21H, and Dowex 50Wx4.
 20. The process ofclaim 13 wherein the dehydration is performed at a temperature of fromabout 98° C. to about 191° C.
 21. The process of claim 13 wherein thedehydration is performed at a temperature of from about 98° C. to about130° C.
 22. The process of claim 13 wherein the dehydration is performedat a temperature of from about 98° C. to about 120° C.
 23. The processof claim 13 wherein the dehydration is performed at a vacuum pressure offrom about 0.01 Torr to about 40 Torr.
 24. The process of claim 13wherein the dehydration is performed at a vacuum pressure of from about0.1 Torr to about 10 Torr.
 25. The process of claim 13 wherein thedehydration is performed at a vacuum pressure of from about 1 Torr toabout 10 Torr.
 26. The process of claim 13 wherein the vacuumdistillation is performed at a vapor temperature of from about 155° C.to about 170° C. and a pot temperature of at least the distilling pointof the dehydrated anhydrosugar alcohol.
 27. The process of claim 13wherein the vacuum distillation is performed at a vapor temperature offrom about 160° C. to about 170° C. and a pot temperature of at leastthe distilling point of the dehydrated anhydrosugar alcohol.
 28. Theprocess of claim 13 wherein the vacuum distillation is performed at avapor temperature of from about 165° C. to about 170° C. and a pottemperature of at least the distillation point of the dehydratedanhydrosugar alcohol.
 29. The process of claim 13 wherein the vacuumdistillation is performed at a vapor temperature of 170° C. and a pottemperature of at least the distillation point of the dehydratedanhydrosugar alcohol.
 30. The process of claim 13 wherein the vacuumdistillation is performed at a vacuum pressure of from about 0.1 Torr toabout 40 Torr.
 31. The process of claim 13 wherein the vacuumdistillation is performed at a vacuum pressure of from about 0.1 Torr toabout 10 Torr.
 32. The process of claim 13 wherein the vacuumdistillation is performed at a vacuum pressure of from about 1 Torr toabout 10 Torr.
 33. A process for the production of purified isosorbide,without the use of organic solvents, the process comprising: heatingsorbitol powder at a temperature of from about 98° C. to about 105° C.,with stirring, until molten; dehydrating the melted sorbitol bycatalysis with an acidic ion exchange resin, added in an amount givingfrom about 0.01 to about 0.15 equivalents, under vacuum pressure of fromabout 1 Torr to about 10 Torr, and while maintaining stirring andtemperature, to form an isosorbide mixture; vacuum distilling thedehydrated isosorbide at a pot temperature of approximately 180° C. anda vapor temperature of approximately 170° C., and a vacuum pressure offrom about 1 Torr to about 10 Torr, to form an isosorbide distillate;melt crystallizing the isosorbide distillate by heating the distillateto at least approximately 65° C. and then cooling the distillate, overfrom about 30 minutes to about 45 minutes, to a temperature of about 25°C. to about 35

C. to form a slurry-like isosorbide solution; centrifuging theisosorbide solution and; collecting the purified isosorbide.